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Do SGLT-2 Inhibitors Change Fat Metabolism?

sharma-obesity-blood-sugar-testing2Since the introduction of SGLT-2 inhibitors (“gliflozins” or “glucoretics), as an insulin-independent treatment for type 2 diabetes, that works by blocking glucose reabsorbtion in the kidney┬áresulting in loss of glucose (and calories) through the kidney, much has been written about the (albeit modest) weight loss associated with this treatment.

Several studies have documented that the weight loss leads to a change in body composition with an often significant reduction in fat mass.

Now, Giuseppe Daniele and colleagues, in a paper published in Diabetes Care, show that treatment with these compounds may enhance fat oxidation and increase ketone production in patients with type 2 diabetes.

The researchers randomized 18 individuals with type 2 diabetes to dapagliflozin or placebo for two weeks.

As expected, dapagliflozin reduced fasting plasma glucose significantly (from 167  to 128 mg/dL).

It also increased insulin-stimulated glucose disposal (measured by insulin clamp) by 36%, indicating a significant increase in insulin sensitivity.

Compared to baseline, glucose oxidation decreased by about 20%, whereas nonoxidative glucose disposal (glycogen synthesis) increased by almost 50%.

Moreover, dapagliflozin increased lipid oxidation resulting in a four-fold increase in plasma ketone concentration and and a 30% increase in fasting plasma glucagon.

Thus, the authors note that treatment with dapagliflozine improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production.

While this may explain the recent observation of a greater (albeit still rather rare) incidence of ketoacidosis with the use of these compounds, these findings may also explain part of the change in body composition previously noted with SGLT-2 treatment.

While this still does not make SGLT-2 inhibitors “weight-loss drugs”, there appears to be more to the fat┬áloss seen with these compounds than just the urinary┬áexcretion of glucose.

@DrSharma
Edmonton, AB

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Metformin Attenuates Long-Term Weight Gain in Insulin-Resistant Adolescents

metformin-300x217The biguanide metformin is widely used for the treatment of type 2 diabetes. Metformin has also been shown to slow the progression from pre to full-blown type 2 diabetes. Moreover, metformin can reduce weight gain associated with psychotropic medications and polycystic ovary syndrome.

Now, a randomised controlled trial by M P van der Aa and colleagues from the Netherlands, published in Nutrition & Diabetes suggests that long-term treatment with metformin may stabilize body weight and improve body composition in adolescents with obesity and insulin resistance.

The randomised placebo-controlled double-blinded trial included 62 adolescents with obesity aged 10ÔÇô16 years old with insulin resistance, who received 2000ÔÇëmg of metformin or placebo daily and physical training twice weekly over 18 months.

Of the 42 participants (mean age 13, mean BMI 30), BMI was stabilised in the metformin group (+0.2 BMI unit), whereas the control group continued to gain weight (+1.2 BMI units).

While there was no significant difference in HOMA-IR, mean fat percentage reduced by 3% compared to no change in the control group.

Thus, the researcher conclude that long-term treatment with metformin in adolescents with obesity and insulin resistance can result in stabilization of BMI and improved body composition compared with placebo.

Given the rather limited effective options for addressing childhood obesity, this rather safe, simple, and inexpensive treatment may at least provide some relief for adolescents struggling with excess weight gain.

@DrSharma
Edmonton, AB

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Zafgen Abandons Belanorib Program But Continues Exploring MetAP2 Inhibitor For Obesity

sharma-obesity-insulin-injectionRegular readers may recall previous posts on the novel anti-obesity compound belanorib, a MetAP2 inhibitor that showed remarkable weight loss efficacy both in patients with Prader-Willi Syndrome as well as hypothalamic obesity.

Unfortunately, as noted before, several cases of venous thromoboembolisms led to a halt of ongoing trials during which the company (Zafgen) sought to better understand the possible mechanism for this serious adverse effect and explore the possibility of implementing a risk mitigation strategy.

As announced by the company in a press release earlier this week,

“Following its discussions with the FDA and review of other considerations, Zafgen has determined that the obstacles, costs and development timelines to obtain marketing approval for beloranib are too great to justify additional investment in the program, particularly given the promising emerging profile of ZGN-1061. The Company is therefore suspending further development of beloranib in order to focus its resources on ZGN-1061.”

The press release also describes the new compound ZGN-1061 as a,

“…fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that was discovered by Zafgen’s researchers and has been shown to have an improved profile relative to previous inhibitors in the class.┬áLike other MetAP2 inhibitors that have shown promise in the treatment of metabolic diseases including severe and complicated obesity, ZGN-1061 modulates the activity of key cellular processes that control the body’s ability to make and store fat, and utilize fat and glucose as an energy source.┬áZGN-1061 is also anticipated to help reduce hunger and restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to weight loss and improved metabolic control. ZGN-1061 has an emerging safety profile and dosage form that are believed to be appropriate for the treatment of prevalent forms of severe and complicated obesity, and is currently in Phase 1 clinical development. Zafgen holds exclusive worldwide rights for the development and commercialization of ZGN-1061.”

According to the press release,

“The compound has similar efficacy, potency, and range of activity in animal models of obesity as beloranib, but displays highly differentiated properties and a reduced potential to impact thrombosis, supporting the value of the compound as a more highly optimized MetAP2 inhibitor.”

Screening of patients for a Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment is currently underway.

@DrSharma
Edmonton, AB

Disclaimer: I have served as a consultant to Zafgen.

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Fructose-Sweetened Beverages Do Not Promote Systemic Inflammation

sharma-obesity-beveragesThere is little doubt that increased consumption of fructose-sweetened beverages can be a substantial source of extra calories, thereby potentially promoting weight gain.

That said, fructose has also been implicated in non-caloric metabolic effects including promoting insulin resistance and systemic inflammation.

Now a study by Jessica Kuzma and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, WA, published in the American Journal of Clinical Nutrition, specifically addresses the hypothesis that fructose-sweetened beverages can promote systemic inflammation.

For their study, they randomised 24 otherwise healthy participants to three 8 day periods during which participants consumed 4 daily servings of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum.

During the study subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight.

Neither fasting plasma concentrations of C-reactive protein or IL-6 changed during the study.

Furthermore, there were no consistent changes in measures of adipose tissue inflammation or in intestinal permeability.

Overall, the researchers conclude that consuming an excessive amount of fructose, HFCS, and glucose derived from SSBs consumed, at least in the short term (8 days), does not appear to promote systemic inflammation in otherwise healthy adults.

Obviously, this study does not address the issue of wether or not overconsumption of sugar-sweetened beverages can promote obesity or whether cutting out such beverages has any other advantages short of lowering caloric consumption.

@DrSharma
Edmonton, AB

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Does Glycemic Response to Food Really Affect Appetite?

GI-Foods-7-HealthA popular narrative by proponents of low-glycemic index foods is the notion that high-glycemic index foods lead to a surge in plasma glucose, which in turn stimulates a spike in insulin levels, resulting in a rapid drop in blood glucose levels and an increase in appetite (“crash and crave”).

While this narrative is both biologically plausible and has been popularised by countless low-GI diets and products, the actual science of whether this story really holds true is less robust that you may think.

Now, a study by Bernd Schultes and colleagues, published in Appetite, seriously challenges this narrative.

The study was specifically designed to test the hypothesis that inducing glycemic fluctuations by intravenous glucose infusion is associated with concurrent changes in hunger, appetite, and satiety.

Using a single blind, counter-balanced crossover study in 15 healthy young men, participants were either given an i.v. infusion of 500 ml of a solution containing 50 g glucose or 0.9% saline, respectively, over a 1-h period.

On each occasion, the infusions were performed one hour after a light breakfast (284 kcal).

I.v. glucose markedly increased glucose and insulin concentrations (peak glucose level: 9.7 vs. 5.3 mmol/l in the control group); peak insulin level: 370 vs. 109) followed by a sharp decline in glycaemia to a nadir of 3.0 in the glucose study vs. 3.9 mmol/l at the corresponding time in the control condition.

Despite this wide glycemic fluctuation in the glucose infusion condition, the subjective feelings of hunger, appetite satiety, and fullness did not differ from the control condition throughout the experiment.

Clearly, these findings speak against the conventional narrative that fluctuations in glycemia and insulinemia represent major signals in the short-term regulation of hunger and satiety.

Or, as the authors put it,

Our findings might also challenge the popular concept of low glycemic index diets to lose body weight. Advocates of this dietary approach often argue that large glycemic (and concurrent insulinemic) fluctuations induced by the intake of high glycemic index foods can trigger feelings of hunger and, thus, on the long run favor weight gain. Our results argue against this notion since the sharp drop in circulating glucose after the end of the glucose infusion remained without effect on hunger ratings, at least within the time period covered by our experiment.

As they further note, these findings may explain why,

“…several clinical dietary intervention trials have failed to show an advantage of low glycemic index dietary approaches for weight loss in overweight/obese subjects in comparison with other dietary approaches.”

The lesson here, I guess is that, just because there is a seemingly compelling narrative to support an idea, it does not mean that that’s how biology in real life actually works.

@DrSharma
Edmonton, AB

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